2-formyl-delta2-9alpha, 11beta-disubstituted androstane derivatives



ilnitecl States Patent p The present invention relates to novelcyclopentanophenanthrene derivatives and to a process for the productionthereof.

More particularly the present invention relates to 2- formy1-A-9a,1lfi-disubstituted androstane derivatives.

The novel compounds of the present invention are represented by thefollowing formula:

In the above formula X may be hydroxyl, fluorine or 'cholorine; Yrepresents fluorine, chlorine or bromine; R

may be hydrogen or a hydrocarbon earboxy-lic acyl group of less than 12carbon atoms; R represents hydrogen, lower alkyl, lower alkenyl or loweralkynyl.

The acyl group is derived from hydrocarbon carboxylic acids containingless than 12 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetate and B-chloropropionate.

The compounds represented by the above formula are strong appetitestimulants and anabolic-androgenic agents with a favorable anabolicratio. In addition the novel compounds exhibit anti-estroganic andanti-gonadotrophic activities and lower the cholesterol level in bloodserum and liver.

The compounds represented by the above formula wherein R representslower alkenyl or lower alkynyl in addition to the foregoing properties,exhibit progestational activity.

The novel compounds of the present invention are prepared by the processexemplified by the following equa- I sten-l7B-ol-3-one (IV).

3,062,849 Patented Nov. 6, 1962 H .11 3 cH,-c-hi 0* IV l.

on on Ho@/ In the above formulas X, Y and 'R have the same meaning aspreviously set forth In practicing the process outlined above thestarting 9(l1)-dehydrotestosterone (I) is reduced with an alkali metalsuch as lithium in liquid ammonia and a proton donor such as ammoniumchloride to afford/W androsten-l7fi-ol-3-one (H). This compound upontreatment with ethyl formate in the presence of an alkali metal hydride,preferably sodium hydride and subsequent acid hydrolysis oi. the formedsodio salt, yields Z-hydroxymethylene-A -androsten-17p-ol-3-one (HI).Reaction of this compound witlra methylating agent, preferablydiazomethane affords Z-methoxymethylene-A" -andro- Reduction of the3-keto group and acid hydrolysis of the resulting 3-hydroxy compoundfurnishes 2-formyl-A -androstadien--01 (V). Upon treatment of thiscompound with a positive halogen ion-negative halogen ion couple, whichmay be a halogen halide generated in situ from'an N-halo-amide-hydrogenhalide mixture, there is formed the corresponding 911,115- dihalocompound (VI) wherein the positive ion is at 90: position. For example,treatment with N-bromoacetamide-hydrogen fluoride gives the 9a-bromo-1lp3-fluoro derivative (VI: Y Br, X F); treatment withN-chlorosuccinimide-hydrogen fluoride yields the 9a-chloro-11{3- fluoroderivative (VI: Y=Cl, X=F).

Following a second sequence of reactions the A androstadiene derivative(V) is treated with N-bromosuccinimide in the presence of perchloricacid to furnish the corresponding 9u-bromo-11/9- hydroxy derivative (VI:Y==Br, X=OH) which upon treatment with a base yields the respective9;3,-l lfi-oxido compound. Opening of the oxide ring with hydrogenfluoride affords the corresponding 9a-fluoro-1lfi-hydroxy derivativeTreatment of a compound selected from the above obtained9al11B-diSubStifllt6d -2-1formy1-A -androstene iderivatives (VI) withethylene glycol in the presence of an acid furnishes the corresponding90:, 11y3-disubstituted-2- ethylenedioxymethyl-A -derivative (VII).

Oxidation of the 2-ethylenedioxymethyl-9a,l'lfi-dihalo- 175-01derivatives (VII: X and Y are halogens of the type previously described)yields the corresponding 2-ethylenedioxymethyl-9a,l1fi-dihalo-17-ketocompound which upon treatment with a lower alkyl, alkenyl, or alkynylmagnesium halide, as for example, methyl magnesium bromide or vinylmagnesium bromide, affords the respective2-ethylenedioxymethyl-9a,1lfi-dihalo-lh-lower alkyl, alkenyl oralkynyl-17B-ol compound (VIII: X and Y are halogens of the previouslydefined type).

Upon oxidation of a 2-ethylenedioxymethyl-9a-halo- 1119,17fi-dihydroxyderivative (VII: X=OH) there is obtained the corresponding 11,17-diketocompound which upon treatment with a lower alkyl, alkenyl or alkynylmagnesium halide yields the correspondingl7a-substituted-17fl-hydroxy-1l-keto compound. Reduction of the ll-ketogroup preferably with sodium borohydride yields the corresponding2-ethylenedioxymethyl-9u-halo-11,6, 17/3-dihydroxy-Not-substitutedderivative (VIII: X=OH).

Treatment of the above obtained Not-substituted compounds, havingpresent in the molecule the Z-ethylenedioxymethyl group, in a mild acidmedium afiords the corresponding 2-formyl compound (IX).

A 2-formyl-9a,1lB-disubstituted-A -androstene derivative described abovehaving a secondary hydroxyl group at the 17,3-position (V1) isconventionally acylated in py ridine with acylating agent as forexample, acetic anhydride or propionic anhydride gives the corresponding171iacyloxy derivative.

The above described 2-formyl-9a,1lfl-disubstituted-A androstenecompounds having a tertiary hydroxyl at the 17/8-position (IX) areconventionally acylated in the presence of p-toluenesulfonic acid withexcess acylating agent, which may be for example, the anhydride of ahydrocarbon carboxylic acid of the type defined hereinbefore, thusyielding the corresponding l7B-acyloxy derivatives.

The following specific example serve to illustrate but are not intendedto limit the scope of the present invention.

Example I A solution of g. of 9(1l)-dehydro-testosterone (Heyl et al.,J. Am. Chem. Soc. 77, 488 (1955), in 100 cc. of dioxane-ether (1:1) wasadded in a steady stream to a solution of 0.5 g. of lithium in 500 cc.of anhydrous liquid ammonia with good stirring. At the end of theaddition the blue color was discharged by the addition of 25 g. ofammonium chloride and the ammonia was allowed to evaporate. The productwas extracted with ether, washed with water, dried and the etherevaporated to afford a gum which was adsorbed from 300 cc. of benzeneonto 250 g. of alumina. Elution with benzene-ether afforded a productwhich upon recrystallization from acetone-hexane gave M-androsten-17B-ol-3-one.

Example II To a solution of 3 g. of the product of Example I in 60 cc.of anhydrous benzene was added 3 cc. of ethyl formate and 1.3 g. ofsodium hydride, suspended in mineral oil while cooling and stirringunder an atmosphere of nitrogen. The mixture was stirred for 24 hours atroom temperature, hexane was added until complete precipitation, thesolid was collected and dried under vacuum. The crude material wassuspended in aqueous hydrochloric acid and stirred at room temperaturefor half an hour. The precipitate was collected, washed with water anddried. Recrystallization from methylene-chloride-hexane gave2-hydroxy-methylene-A -androsten-l-ol-3-one.

Example III To a solution of 3 g. of the product of Example II in 50 cc.of methylene chloride were added an excess of diazomethane in ether(obtained from nitrosomethylurea) and a few drops of methanol. Thereaction mixture was kept at room temperature for 18 hours. The excessreagent was decomposed with acetic acid. The resulting mixture waspoured into water, the organic layer washed to neutral and evaporated todryness. Recrystallization from acetone-hexane affordedZ-methoxymethylene-A" androsten-l7B-ol-3-one.

Example IV A solution of 2 g. of sodium borohydride in 6 cc. of waterwas added to an ice-cooled solution of 2 g. of the product of ExampleIII in 220 cc. of methanol and the mixture was allowed to stand for 16hours at room temperature. The excess reagent was decomposed by additionof acetic acid, the solution was further acidified with 1 cc. ofconcentrated hydrochloric acid and stirred for 30 minutes at roomtemperature, then it was concentrated to small volume in vacuo anddiluted with water. The product was extracted with ethyl acetate, theextract was washed with water, dried and evaporated. The solid residuewas purified by crystallization from acetone-hex ane to give 2-formyl-A-androstadien1713-01.

Example V To a polyethylene bottle containing 119 g. of anhydroustetrahydrofuran was added 70 g. of anhydrous hydrogen fluoride. Themixture was cooled to 70 C. in a Dry Ice-acetone bath and, undervigorous stirring there was added a mixture, previously cooled to 70 C.,of 10 g. of 2-formyl-A (11) androstadien-175-01 obtained according tothe foregoing example, and 5.0 g. of N-bromo' acetamide in 350 m1. ofanhydrous methylene chloride distilled over calcium chloride. Themixture was stirred at 70 C. for 5 hours, poured into aqueous saturatedsodium carbonate solution and the precipitate was filtered. The organiclayer was separated, the aqueous phase was extracted with severalportions of methylene chloride and the extracts were combined, Washedwith water to neutrality, dried over anhydrous sodium sulfate andevaporated to dryness under vacuum. The original precipitate and theresidue of the evaporation were combined and crystallized from acetone,thus affording 2 formyl-9a-bromo- 1 l ,fi-fluoro-A -androsten- 1 75-01.

Example VI To 120 cc. of a saturated solution of hydrogen chloride intetrahydrofuran were added with vigorous stirring 10 g. of 2-formyl-A-androstadien-l7,8-01 obtained according to Example IV, and 5.0 g. ofN-bromoacetamide in 350 ml. of anhydrous methylene chloride distilledover calcium chloride. The mixture was stirred at 0 C. for 5 hours,poured into aqueous saturated sodium carbonate solution and theprecipitate was filtered. The organic layer was separated, the aqueousphase was extracted with several portions of methylene chloride and theextracts were combined, washed with water to neutrality, dried overanhydrous sodium sulfate and evaporated to dry ness under vacuum. Theoriginal precipitate and the residue of the evaporation were combinedand crystallized from acetone, thus affording 2-f0rmyl9a-bromo-1 1,6-chloro-A -androsten-175-01.

Example VII Following exactly the procedure described in Example Vexcept that N-bromoacetamide was substituted by N- chlorosuccinimide,there was obtained 2-formyl-9a-chloro- 1 1 p-fluoro-u -androsten-175-01.

Example VIII Following the procedure described in Example VI except thatN-bromoacetamide was substituted by N-chlorosuccinimide, there wasobtained 2-formyl-9a,llfi-dichloro- A -androsten-l7B-ol. I

Example IX 2.8 g. of N-bromoacetamide were added to a mixture of 5 g. of2-formyl-A -androstadien-l718-01, 50 cc. of pure dioxane and 0.8 cc. of0.4 N perchloric acid while stirring in the dark and at room temperatureduring one hour. The reaction mixture was stirred for one hour further,.a solution of 10% sodium sulfite was then added until thepotassium-starch indicator paper no longer turned blue, ice was added,the mixture was extracted with chloroform and the extract was washedconsecutively with water, 5% aqueous sodium bicarbonate solution andwater, and the solvent was removed by distillation under vacuo. Bytrituration of the residue with acetone there was obtained2-formy1-9a-brom0-A -androstene-l 1,8,17fl-diol.

Example X A mixture of 2 g. of anhydrous potassium acetate and 20 cc. ofacetone was heated almost to boiling and then a solution of 1.7 g. ofthe above bromohydrin of Example IX in 20 cc. of acetone was addedslowly while stirring; the mixture was then refluxed for 10 hours,cooled and almost all of the acetone was distilled off; iced-water wasthen added, the precipitate was filtered, washed with water and dried.Upon recrystallization from methylene chloride-benzene there wasobtained 2- formyl-9;8,1lfl-oxido-A -androsten-17 8-01.

Example XI In a polyethylene flask, adapted with magnetic stirrer, therewas dissolved 1.8 g. of the oxido product of Example X in 30 cc. ofmethylene chloride, the solution was cooled to C. and a solution of 2.11g. of anhydrous hydrogen fluoride in 3.7 cc. of tetrahydrofuran cooledin a Dry-Ice acetone bath (70 C.) was added over a period of 20 minuteswith constant stirring. The mixture was stirred at a temperature lowerthan 10 C. for 6 additional hours, then neutralized by cautiously addinga aqueous sodium bicarbonate solution and transferred to a separatoryfunnel. The organic layer was washed with water, dried over anhydroussodium sulfate and concentrated until formation of an abundantprecipitate. The mixture was cooled, the precipitate filtered andredissolved in hot ethyl acetate, the insoluble material was filteredoff and the filtrate cooled whereby there crystallized2-formyl-9a-fluoro-A -androstene-11B, l7fl-di0l.

Example XII A mixture of g. of 2-formyl-9u-bromo-1lit-fluoro- A-andr0sten-17 3-0l, 250 cc. of dry benzene, 50 cc. of ethylene glycoland 500 mg. of p-toluenesulfonic acid monohydrate was refluxed for 16hours using a water separator. It was then washed with a sodiumbicarbonate solution, water and subsequently dried and evaporated todryness. Recrystallization from acetone-hexane yielded 2ethylenedioxymethyl 9a bromo 11p fluoro A androsten-17fl-ol.

6 Example XIII 2 formyl 9a bromo 11p chloro A androsten- 17,8 ol, 2formyl 9a chloro 11B fluoro A androsten 17/3 ol, 2 formyl 904,11fldichloro A androsten-17 801 and 2-formyl-9u-flu0ro-A -androsten-11,8, l73-diol were treated following the technique described in the foregoingexample affording correspondingly 2- ethylenedioxymethyl 90c bromo 11Bchloro A androsten 17,3 -ol, 2 ethylenedioxymethyl 9a chloro- 115 fiuoroA androsten 17p ol, 2 ethylenedioxymethyl-9a,llp-dichloro-d-androsten-l7 8-01 and 2-ethylenedioxymethyl-9a-fiuoro-A -androsten-1113,17fi-di0l.

Example XIV A solution of 6 g. of 2-ethylenedioxymethyl-9a-bromo- 1lS-fiuoro-M-androsten-l7,8-01 in 120 cc. of pyridine was added to amixture of 6 g. of chromic trioxide in 120 cc. of pyridine. The reactionmixture was kept at room temperature overnight. It was then diluted withethyl acetate, filtered through celite and the filtrate washed well withwater, dried and evaporated to dryness. Crystallization fromacetone-hexane aiforded 2-ethylenedioxy methyl-9a-bromo-1113-fluoro-A2-androsten-17-one.

Following the same procedure there were treated 2-ethylenedioxymethyl-9u-bromo 11 3 chloro A androsten-17B-ol,2-ethylenedioxyrnethyl 9a chloro-11flfluoro-A -androsten-175-01,2-ethylenedioxymethyl 90c, 1'1fl-dichloro-A -androsten-17(5' ol and2-ethylenedioxymethyl-9a-fluoro-A -androsten-115,17B-diol, yieldingrespectively 2-ethylenedioxymethyl-9a-bromo-1lp-chloro- A-androsten-17-one, 2-ethylenedioxymethyl-9a chloro- 1lfi-fluoro-A-androsten-17-one, 2 ethylenedioxymethyl- 9a,11fl-dichloro-u-androsteml7-one and 2-ethylenedioxy- 3 5. methyl-9-a-fiuoro-A-androsten-11,17-dione.

Example XV A solution of 5 g. of Z -ethyIenedioXymethyI-Su-bromo- 1lflfluoro-A -androsten-l7-one in 250 cc. of tiophenefree benezene wastreated with 27.5 cc. of 4 N methylmagnesium bromide in ether and themixture refluxed with the exclusion of moisture for 3 hours. The cooledmixture was cautiously treated with excess aqueous ammonium chloridesolution and the product isolated by ethyl acetate extraction. Theextract was washed with water, dried over anhydrous sodium sulfate'andevaporated to dryness.

Recrystallization from methylene chloride-hexane afforded2-ethylenedioxymethyl-9a bromo-1lfi-fluoro-lhmethyl-M-androsten-l7 8-01.

The starting compounds listed below were treated with the indicatedmagnesium bromide following the above technique, thus yielding thecorresponding products hereinafter disclosed.

Starting compound Grignard reagent; Product Starting compound Product2-ethylenodioxy- Vinyl magnesium2-ethylcnedioxymethylrncthyl-9a-bromobromide. a-CillOIO-llfl-fillOl'D-2-ethylcnodioxymcthyl-tla-fluoro- 2-formyl-9a-tlu0ro-17or-methyl-A lfloo- 17a: vinyl-A l7a-methyl-M-nndrosten-llfl, an lrosten-llfl,l7fl-(liolandrosten-17-onet androsten-l75-ol. 17541101 2-ethylenedioxy Methylmagnesium 2-eth'ylenedioxynietliyl- 2-ethylcncdioxymethylat fluoro-2-formyl-9a-fluoro-17a-vinyl-A rnethyl-JaJl S- bromide.QuJIB-dichloro-Ha- 17m-Vinyl-A -androsten4lfl,17B- androstcn-llfidm-dioldichloro-A -andromethyl-N-androstendiol sten-l7-one. 176-01.2-ethylenedioxymethyl-9a-fluoro- 2-formyl-9a-Iluoro17 -othinyLA Do Vinylmagnesium 2-ethylenodioxymethyl- 17a-ethinyl-A androsten-Ufi,androstcn-lldflfl-drol bromide. 9a,11B-dichloro-17a- 17B-diolvinyl-N-androsten- 10 D E hi 1 i 2 g i d n 1 o t ny magnes um -e ycneioxyme 1y bromide. QafiEfl-IGiChlOEhO-UII- Example XVIII et y -A -anosten- 2 m1 dl M h 1 i Ugo]. (11 t1 1 A mixture of l g. of2-formyl-9a-bromo-llfi-fluoro- -e yene oxyat y magnes um 2-et yene oxyme1y z methybgwfluow momma gmfluomdmmemyb 1 A -andr osten-17B-ol, 4 cc. ofpyridine and 2 cc. of acetic Af-ondrosten-ILH- N-androsten-Ufloh aanhydride was kept at room temperature overnight, fifj Vinyl magnesiumpoured into ice water, the formed precipitate was filtered,

bromide. s -fluoro-imvinyiwashed with water and dried. Crystallizationfrom acefijfgfigf tone-hexane gave the l7-acetate of 2-formyl-9a-bromo-D0 Ethinylneeneslum y e r y llfi-fluoro-A -androsten-l75-01.

bmml Z.'.,;%Zg3f fii 20 By the same procedure were treated2-formyl-9abromo 11B chloro A androsten-175-ol, 2-formyl-9uchloro1lfl-fiuoro-A -androsten-175-01, 2-formyl-9a,llp-

Example XVI 2-ethylenedioxymethyl-9a-fluoro 17a methyl A- androsten 17 3ol l1 one, 2 ethylenedioxymethyl 9o: flllOl'O-17oc-ViIlY1-A androsten17p-ol-l=1-one, and 2- ethylenedioxymethyl-9a-fluoro-l7a-ethinyl-Aandrosten' 173-01-1 l-one were reduced with sodium borohydride followingthe technique described in Example IV with the exception that thereaction mixture was not acidified, thus furnishing correspondingly2-ethylenedioxymethyl 9mfluoro-l7a-methyl-A -androsten 11$,17fi-dio1,2-ethylenedioxymethyl-9a-fiuoro-17m-vinyl A androsten-11[3,17B- diol,and 2 ethylenedioxymethyl-9a-fiuoro-17a-ethiny1- A -androsten-l 13,17fldiol.

Starting compound Product dichloro-A -androsten--01, and2formyl-9a-fiuoro-A androsten-ll/3,l7;8-diol yielding correspondinglyl7-acetate of 2-formyl-9a-bromo-1lfl chloro-A -androsten-1713- ol,l7-acetate of 2-formyl-9'a-chloro-llfl-fluoro-A -androsten-l7fi-ol,l7-acetate of 2formyI-9a,1lfi-dichloro- A -androsten-17/3-ol andl7-acetate of 2-formyl-9u-fluoro- A -andrOsten-l 15,17,8-diol.

Example XIX Following the procedure described in the foregoing exampleexcept that acetic anhydride was substituted by propionic anhydride,caproic anhydride, cyclopentyl propionic anhydride and benzoyl chloridethere were correspondingly obtained the 17-.propionates, l7-caproates,17-cyclopentylpropionates and 17-benzoates of the starting compounds ofthe said example.

Example XX A mixture of l g. of 2-formyl-9a-bromo-11/3-fluoro-17a-methyl-A -androsten-17,8-01, l g. of p-toluenesulfonic acidmonohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydride waskept for 24 hours at room temperature. It was then poured into water andstirred until the excess of anhydride had hydrolyzed. Isolation of theproduct by methylene chloride extraction and crystallization of theresidue from acetone-ether gave a mixture of the l7-acetate of thestarting compound and the l7-acetate of Z-acetoxymethylene 9a bromo-ll/i-fiuoro-17amethyl-A -androsten-17 3-01. This mixture was dissolved in20 cc. of methanol and 5 cc. of tetrahydrofuran and was added to 5 cc.of cold 2% methanolic potassium hydroxide. The solution was kept at 0-5C. for 1 hour and then poured into water and neutralized with dilutehydrochloric acid. Ether extraction furnished a product which aftercrystallization from acetone-hexane gave the pure 2 formyl 9oz bromo-lIii-fluoro-17a-methyl-A -androsten-l7B-ol acetate.

Starting compound Product 2'tormyl-9u-bromo-11fi-tluoro-l7avinyl-Aandrostcn-178-01.

2 lormy1-9a-bromo-l1B-chloro-17avinyln- -androsten-lm-ol.

2-formyl-9a-bromo-11B-chloro-17aethinyl-A -androsten-l7,901.

Starting compound Product dichloro-l7a-vlnyl-A -androsten- Z-IOrmyl-ll-chloro- Example XXI The starting compounds of the foregoing examplewere treated following the technique described in the same exampleexcept that acetic anhydride was substituted by propionic anhydride,caproic anhydride and cyclopentylpropionic anhydride thus furnishing thecorresponding 17-propionates, 17-caproates and17-cyclopentylpropionates.

We claim:

1. A compound of the following formula:

sten-17;S-ol.

8. 2-formyl-9 -bromo-l lfl-chloro-17r-vinyl-A androsten-17fi-ol.

10. 2-formyl-9a,1lfi-dichloro-17a-methyl-A -androsten- 17fl-ol.

11. 2-formyl-9m-fluoro-l7a-methyl-A androsten 115, 17 ,B-diol.

12. 2-formyl-9e-fluoro-17a-ethyuyl-A3 androsten 11B, 17fi-diol.

13. The l7-est ers derived from hydrocarbon carboxylic acids of lessthan 12 carbon atoms of 2-formyl-9a-bromo- 1 1fl-fluoro-A-androsten-l7a-ol.

14. The 17-esters derived from hydrocarbon carboxylic acids of less than12 carbon atoms of 2-f0rmyl-9a-bromo- 1 1 fl-fiuoro-l 7a-methyl-A-androsten--01.

15. The 17-esters derived from hydrocarbon carboxylic acids of less than12 carbon atoms of 2-formyl-9a-fiuoro- 17a-ethynyl-A -androsten-llfl,17p-diol.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: